Pharmaceutical formulation of palbociclib and a preparation method thereof

ABSTRACT

The present invention belongs to the pharmaceutical field, and in particular, it relates to a pharmaceutical formulation of palbociclib and a preparation method thereof. The pharmaceutical formulation comprises palbociclib, an acidic auxiliary material, and optionally a hydrophilic high-molecular material, which has better solubility and in vitro dissolution property as compared with the conventional formulation and can be used for enhancing in vivo absorption and bioavailability of palbociclib.

CROSS-REFERENCE

This application is a continuation of Ser. No. 16/554,112 filed Aug. 28,2019, issued as patent no. 10,813,937 on Oct. 27, 2020, which is acontinuation application of Ser. No. 15/613,853 filed Jun 5, 2017,issued as U.S. Pat. No. 10,449,195 on Oct. 22, 2019, which is acontinuation application of PCT/CN2016/086546 filed Jun. 21, 2016, whichclaims the benefit of priority to CN 201610187046.8 filed Mar. 29, 2016,each of which is entirely incorporated herein by reference.

TECHNICAL FIELD

The present invention belongs to the pharmaceutical field. Morespecifically, the present invention relates to a pharmaceuticalformulation of palbociclib and a preparation method thereof. Thepalbociclib of the present invention may be a palbociclib free base orany of its pharmaceutically acceptable salts.

BACKGROUND ART

World Health Organization statistics show that breast cancer is theworld's second cause of cancer deaths in women. Over the past fewdecades, the incidence of breast cancer showed an increasing trend. Itis expected that by 2020, there will be more than 1.7 million new casesof breast cancer each year. By 2012, there are 1.67 million new cases ofbreast cancer worldwide, accounting for 25% of all new cases of cancer,wherein 883,000 cases are in developed countries and 794,000 cases arein developing countries. The growth rate of new cases of breast cancerin developing countries is slightly higher than that in developedcountries. There are 522,000 cases of breast cancer deaths, rankingfifth in lethality rate in all cancers. In underdeveloped areas, thebreast cancer causes 324,000 women deaths, accounting for 14.3% of allcases of cancer deaths, and is the most frequent lethal cancer. Indeveloped areas, there are 198,000 cases of breast cancer deaths inwomen, accounting for 15.4% of all cases of cancer deaths, second onlyto lung cancer. Therefore, breast cancer is still one of the world'simportant health problems.

According to the international patent WO2003/062236, palbociclib is aninhibitory agent for cyclin-dependent kinases (CDKs) 4 and 6, whichinhibits the synthesis of DNA primarily by preventing cells from G1phase to S phase via the inhibition of CDK4/6 activity, and can be usedto treat metastatic breast cancer. Clinical trial studies have shownthat palbociclib combined with letrozole is very effective inpostmenopausal patients with locally infiltrating breast cancer or innewly diagnosed estrogen receptor (ER)-positive and HER-2-negativepatients. Its chemical structure is as follows:

The structure and preparation method of said compound and its salts havebeen described in the international patent WO2003/062236 and U.S. Pat.No. 6,936,612. The preparation methods of free bases and salts ofvarious acids are also described in the international patent applicationWO2005/005426 and U.S. Pat. Nos. 7,345,171 and 7,863,278. According tothe description in the international patent application WO2005/005426,the solubility of the palbociclib free base in water is poor, whichleads to a low bioavailability and is disadvantageous for the absorptionin human body. The free base has a strong adhesive property upon impact,and said adhesive property is related to the specific surface area ofthe particles, so its particle size must be controlled in a certainrange. According to the international patent application WO2014128588,it is necessary to use an active pharmaceutical ingredient (API) ofpalbociclib free base having a larger particle size in order to improvethe physichemical properties and the capacity to produce a formulationproduct. If the palbociclib free base is reacted with an acid togenerate salts so as to increase the solubility, the salts have a poorsolid nature and thereby are disadvantageous for being developed as asolid formulation, according to the reports in the previously knownpatents.

At the same time, palbociclib is an insoluble drug. At present,palbociclib has been approved for sale in the United States. Accordingto the instructions for the approved product of palbociclib in theUnited States, one of seven patients has poor absorption uponadministration of the palbociclib product. For these patients, theefficacy of said product will be relatively low. It is likely that thepoor solubility of the drug causes the poor absorption in some patients.Thus, in the present, it is very necessary to further improve the dosageform of palbociclib so as to increase the dissolution rate andbioavailability thereof.

SUMMARY OF THE INVENTION

It is an object of the present invention to develop a novelpharmaceutical product for improving the dissolution and bioabsorptionof palbociclib. According to the prior art and common knowledge, it isgenerally considered that the in vitro dissolution of an oral solidformulation product of an insoluble drug has a certain correlation withits in vivo absorption. Thus, an in vitro dissolution method is employedin the present invention to assess the capacity of the formulationproduct to be absorbed in vivo.

The present invention has surprisingly found that the dissolution of theoral solid formulation product prepared by mixing the API of palbociclibwith a pharmaceutically acceptable acidic auxiliary material andoptionally adding another pharmaceutically acceptable excipient can besignificantly increased relative to the oral solid formulation productsprepared in the prior art.

The present invention has also surprisingly found that, the disadvantagethat the API having a small particle size cannot be used for thepreparation of formulations as disclosed in the international patentapplication WO2014128588 can be overcome by pulverizing the API ofpalbociclib to reduce its particle size to D90 at 20 μm or less and thenmixing with a pharmaceutically acceptable acidic auxiliary material, orby mixing the API of palbociclib with the pharmaceutically acceptableacidic auxiliary material, co-pulverizing to reduce the particle size ofthe mixture to D90 at 20 μm or less, and optionally adding anotherpharmaceutically acceptable excipient; and after an oral dosage form isprepared, the in vitro dissolution can be significantly increased.

The present invention has also surprisingly found that the API ofpalbociclib and the pharmaceutically acceptable acidic auxiliarymaterial can be co-dissolved in a solvent and the concentration of theAPI of palbociclib in the solvent can be up to 50 mg/ml or more; andwhen a hydrophilic high-molecular material is further added anddissolved evenly and the solvent is removed by volatilization, anamorphous solid dispersion is formed. After an oral solid formulationproduct is prepared by optionally further adding anotherpharmaceutically acceptable excipient, its dissolution is furthersignificantly increased.

The present invention has also surprisingly found that the method forpreparing a solid dispersion of the present invention can also convertthe acidic auxiliary material into an amorphous state and the amorphousstate can be maintained for a long period of time, which is advantageousfor maintaining the amorphous state of the API of palbociclib.

In the invention, by adding the acidic auxiliary material, reducing theparticle size of the API of palbociclib and making the palbociclib in anamorphous manner, the in vitro dissolution of palbociclib is increased,and thereby its in vivo bioavailability can be improved.

In particular, the present invention provides a pharmaceuticalformulation of palbociclib, which comprises a palbociclib free base or apharmaceutically acceptable salt thereof and an acidic auxiliarymaterial.

In one embodiment, the palbociclib free base or the salt thereof is asolid.

In one embodiment, the particle size (D90) of palbociclib in thepharmaceutical formulation is 20 μm or less.

In one embodiment, the particle size (D90) of palbociclib and the acidicauxiliary material in the pharmaceutical formulation is 20 μm or less.

In one embodiment, the acidic auxiliary material is one or more selectedfrom the group consisting of a pharmaceutically acceptable water-solubleorganic acid or a hydrate or an acidic salt thereof, a water-solubleacidic amino acid or a hydrate or an acidic salt thereof, an acidic saltof a water-soluble amino acid or a hydrate thereof, or an acidic salt ofa water-soluble inorganic acid or a hydrate thereof.

In one embodiment, the water-soluble organic acid is one or moreselected from the group consisting of tartaric acid, fumaric acid,succinic acid, citric acid, lactic acid and malic acid; thewater-soluble acidic amino acid is one or more selected from the groupconsisting of glutamic acid and aspartic acid; the acidic salt of awater-soluble amino acid is one or more selected from the groupconsisting of the acidic salts of glycine, alanine and serine; and theacidic salt of the water-soluble inorganic acid is one or more selectedfrom the group consisting of dihydric phosphate and bisulfate.

In one embodiment, the acidic auxiliary material is preferably one ormore selected from the group consisting of tartaric acid, fumaric acid,succinic acid, citric acid, lactic acid and malic acid, more preferablytartaric acid.

In one embodiment, the mass ratio of the acidic auxiliary material topalbociclib is from 0.2:1 to 5:1, preferably from 0.5:1 to 2:1.

In one embodiment, the pharmaceutical formulation is a tablet orcapsule.

In one embodiment, the dosage of the tablet or capsule is from 25 mg to500 mg, preferably from 50 mg to 150 mg.

The present invention also provides a solid dispersion of palbociclib,which comprises a palbociclib free base or a pharmaceutically acceptablesalt thereof, an acidic auxiliary material and a hydrophilichigh-molecular material.

In one embodiment, the hydrophilic high-molecular material is one ormore selected from the group consisting of povidone K30 (PVP-K30),copovidone VA64 (PVP-VA64), Soluplus, hydroxypropylmethylcellulose E5(HPMC-E5), hydroxypropylmethylcellulose acetate succinate (HPMC-AS -HF),hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin.

In one embodiment, the acidic auxiliary material is selected from one ormore pharmaceutically acceptable organic acids and optionally one ormore pharmaceutically acceptable inorganic acids. Among them, thepharmaceutically acceptable organic acid is preferably selected from thegroup consisting of tartaric acid, fumaric acid, succinic acid, citricacid, lactic acid, malic acid, aliphatic sulfonic acids (e.g.,methanesulfonic acid, ethanesulfonic acid, isethionic acid, etc.) andaromatic sulfonic acids (e.g., benzenesulfonic acid, p-toluenesulfonicacid, etc.), and the pharmaceutically acceptable inorganic acid ispreferably selected from the group consisting of hydrochloric acid,sulfuric acid, phosphoric acid and the like. In the present invention,“optionally” means that the pharmaceutically acceptable inorganic acidcan be present or absent and, if the pharmaceutically acceptableinorganic acid is present, the amount of the pharmaceutically acceptableorganic acid can be reduced.

In one embodiment, the mass ratio of the hydrophilic high-molecularmaterial to palbociclib is from 0.1:1 to 10:1, and the mass ratio of theacidic auxiliary material to palbociclib is from 0.2:1 to 5:1;preferably, the mass ratio of the hydrophilic high-molecular material topalbociclib is from 1:1 to 3:1, and the mass ratio of the acidicauxiliary material to palbociclib is from 0.5:1 to 2:1.

The present invention also provides a method for the preparation of apharmaceutical formulation, comprising: mixing an API of palbociclibwith a pharmaceutically acceptable acidic auxiliary material, preferablyat a certain mass ratio, and further, optionally adding anotherpharmaceutically acceptable excipient.

The present invention also provides another method for the preparationof a pharmaceutical formulation, comprising: pulverizing the API ofpalbociclib to control the particle size at 20 μm or less, and thenmixing with the pharmaceutically acceptable acidic auxiliary material,or adding the acidic auxiliary material to the API, mixing andco-pulverizing to control the particle size at 20 μm or less; andfurther, optionally adding another pharmaceutically acceptableexcipient.

The present invention also provides a method for the preparation of asolid dispersion, comprising: mixing palbociclib with an acidicauxiliary material; adding a solvent (including but not limited towater, ethanol, acetone and a mixture thereof, preferably water or amixture thereof with other solvents, e.g. the mixture of water andethanol, the mixture of water and acetone, etc.) for dissolving ordispersing; adding a hydrophilic high-molecular material, dissolving ordispersing evenly; and removing the solvent by heating, for example,evaporating the solvent to dry by vacuum drying or heating drying orfreeze drying or other drying ways, in order to achieve the purpose ofdispersing the drug in the high-molecular solid carrier to a highdegree, so as to prepare the solid dispersion.

In the preparation of the solid dispersion of the present invention, theconcentration of the API of palbociclib in the solvent (e.g., water) canbe up to 50 mg/ml or more, thereby improving the preparation efficiencyof the solid dispersion.

The present invention also provides the use of a pharmaceuticalformulation or a solid dispersion for the treatment of breast cancer.

In the present invention, palbociclib refers to a palbociclib free baseor a pharmaceutically acceptable salt thereof, which can be usedinterchangeably.

For those skilled in the art, the excipient is well known and may be anadhesive, a filler, a disintegrant, a lubricant, a preservative, anantioxidant, a flavoring agent, a fragrance, a cosolvent, an emulsifier,a solubilizer, an osmotic pressure regulator, a coloring agent and thelike.

In the present invention, palbociclib is pulverized, or the palbociclibis mixed with the acidic auxiliary material and co-pulverized, forexample, by means of the airflow pulverization technique, in order toreduce the particle size to D90 at 20 μm or less.

In the present invention, the pharmaceutical formulation is an oralsolid formulation product, such as a tablet or a capsule. Such a productis generally prepared by mixing the API with another pharmaceuticallyacceptable auxiliary material, such as an excipient, a lubricant, adisintegrant and the like, so as to prepare the oral solid formulationproduct. The palbociclib oral solid formulation product which has beenapproved for sale in the United States (the trade name is Ibrance), wasmanufactured by the above-mentioned technique, according to thedescription in its drug instructions.

The present invention successfully prepares the solid dispersion ofpalbociclib for the first time by means of a special combination. In theprior art, the solid dispersion is a kind of formulation technique, anduseful for a formulation product of an insoluble drug. Usually, anamorphous solid dispersion is prepared from the insoluble API togetherwith a hydrophilic pharmaceutical high-molecular auxiliary material. Themethods for the preparation of the amorphous solid dispersion include asolvent method and a melting method. The solvent method includesdissolving the API and the auxiliary material together in a solvent andthen volatilizing the solvent. The melting method includes co-meltingthe API and the high-molecular auxiliary material and rapidly coolingthe same. In view of the high melting point of palbociclib, reaching271° C., and the insolubility in most of solvents, it is impossible toprepare the amorphous solid dispersion in accordance with the soliddispersion technique in the prior art.

In the present invention, the formulation prepared by mixing the API ofpalbociclib with the acidic auxiliary material exhibits a cumulativedissolution rate of 47.8% in a dissolution medium at pH 6.0 for 60minutes, increased from 34.0% of the product prepared by the priorformulation technique (FIG. 1).

Further, the formulation prepared by pulverizing palbociclib (having aparticle size at 20 μm or less, FIG. 2), or the formulation prepared bymixing and co-pulverizing palbociclib and the acidic auxiliary materialexhibits a further increased cumulative dissolution rate of 66.6% and68.7%, respectively, at pH 6.0 for 60 minutes (FIG. 3).

Further, the solid dispersion prepared by mixing the API of palbociclibwith the acidic material and then with the hydrophilic high-molecularmaterial, exhibits a dynamic solubility of 85%, increased from 58% ofthe API of palbociclib itself, as shown in a dynamic solubility testperformed in a buffer at pH 6.0 with stirring for 60 minutes (FIG. 4).

The preparation method of the solid dispersion of the present inventioncan also convert the acidic auxiliary material such as tartaric acidinto an amorphous state (FIG. 5) and the amorphous state is maintainedover one week of storage in a stabilizing box at 40° C./75% RH, which isadvantageous for maintaining the amorphous state of the palbociclibsolid dispersion for a long period of time.

DESCRIPTION OF DRAWINGS

In order to clearly describe the technical solutions of the presentinvention, a brief description will be given below with reference to thedrawings. It is apparent that these drawings merely represent somespecific embodiments described in the present application. The inventionincludes, but not limited to, the following drawings.

FIG. 1 shows the in vitro dissolution of the capsule formulationprepared from palbociclib with the acidic auxiliary material or withoutthe acidic auxiliary material;

FIG. 2 shows the particle size of the pulverized palbociclib;

FIG. 3 shows the in vitro dissolution of the capsule formulationprepared by mixing the pulverized palbociclib with the acidic auxiliarymaterial, and of the capsule formulation prepared by co-pulverizing theAPI of palbociclib and tartaric acid to reduce the particle size;

FIG. 4 shows the dynamic solubility of the solid dispersion prepared bymixing the API of palbociclib with the acidic material and then with ahydrophilic high-molecular material, compared to the API of palbociclibitself, as tested in a buffer at pH 6.0 with stirring for 60 minutes;

FIG. 5 shows the amorphous state of the acidic auxiliary materialtartaric acid in the solid dispersion of the present invention;

FIG. 6 shows an XRPD pattern of the API of palbociclib used in thepresent invention;

FIG. 7 shows an XRPD pattern of a palbociclib solid dispersion preparedwith HPMC-AS-HF;

FIG. 8 shows an XRPD pattern of a palbociclib solid dispersion preparedwith PVP-VA64;

FIG. 9 shows an XRPD pattern of a palbociclib solid dispersion preparedwith PVP-K30;

FIG. 10 shows an XRPD pattern of a palbociclib solid dispersion preparedwith Soluplus; and

FIG. 11 shows an XRPD pattern of a palbociclib solid dispersion preparedwith HPMC-E5.

DESCRIPTION OF EMBODIMENTS

To further understand the present invention, preferred embodiments ofthe present invention will be described below with reference toexamples. These descriptions are merely illustrative for features andadvantages of the novel pharmaceutical formulation of the presentinvention, without limiting the scope of the present invention.

Example 1 Preparation of the Capsule Dosage Form from the AcidicAuxiliary Material and Palbociclib by Dry Granulation and Filling

1500 mg of the API of palbociclib, 345 mg of lactose, 1200 mg oftartaric acid, 840 mg of microcrystalline cellulose, 210 mg of sodiumcarboxymethyl starch and 84 mg of silica were weighed and mixed in athree dimensional mixer for 15 minutes, then 21 mg of magnesium stearatewas added and mixed for another 2 minutes in the three dimensionalmixer. After mixing, the mixture was passed through a 40-mesh sieve andtableted with a mechanical single-punch tableting machine at a pressureof 5 MPa, each tablet weighing 1050 mg. The pressed large tablets werecrushed and passed through a 10-mesh sieve, and dispensed into gelatincapsules at a loading of 350 mg per capsule. The dissolution rate wasmeasured at pH 6.0 and at the selected time points of 5, 10, 15, 20, 30,45 and 60 minutes.

At the same time, a comparative test without the acidic auxiliarymaterial was performed in parallel. 1500 mg of the API of palbociclib,1545 mg of lactose, 840 mg of microcrystalline cellulose, 210 mg ofsodium carboxymethyl starch and 84 mg of silica were weighed and mixedin a three dimensional mixer for 15 minutes, then 21 mg of magnesiumstearate was added and mixed for another 2 minutes in the threedimensional mixer. After mixing, the mixture was passed through a40-mesh sieve and tableted with a mechanical single-punch tabletingmachine at a pressure of 5 MPa, each tablet weighing 1050 mg. Thepressed large tablets were crushed and passed through a 10-mesh sieve,and dispensed into gelatin capsules at a loading of 350 mg per capsule.The dissolution rate was measured by a basket method at pH 6.0, at arotation speed of 100 rpm and at the selected time points of 5, 10, 15,20, 30, 45 and 60 minutes.

The measurement results of the dissolution of the capsules with theacidic auxiliary material and without the acidic auxiliary material wereillustrated by the two curves in FIG. 1 respectively.

Example 2 Preparation of a Capsule by Mixing the Acidic Material withPalbociclib, Followed by Pulverization, and Dry Granulation and Filling

1500 mg of the API of palbociclib, which had been pulverized by airflow,was weighed and mixed with 1200 mg of tartaric acid, 345 mg of lactose,840 mg of microcrystalline cellulose, 210 mg of sodium carboxymethylstarch and 84 mg of silica in a three dimensional mixer for 15 minutes.Then, 21 mg of magnesium stearate was added and mixed for another 2minutes in the three dimensional mixer. After mixing, the mixture waspassed through a 40-mesh sieve and tableted with a mechanicalsingle-punch tableting machine at a pressure of 5 MPa, each tabletweighing 1050 mg. The pressed large tablets were crushed and passedthrough a 10-mesh sieve, and dispensed into gelatin capsules at aloading of 350 mg per capsule. The dissolution rate was measured by abasket method at pH 6.0, at a rotation speed of 100 rpm and at theselected time points of 5, 10, 15, 20, 30, 45 and 60 minutes. Theairflow co-pulverized mixture of the API of palbociclib and tartaricacid (comprising 1500 mg of palbociclib and 1200 mg of tartaric acid)was added with 345 mg of lactose, 840 mg of microcrystalline cellulose,210 mg of sodium carboxymethyl starch and 84 mg of silica, and mixed ina three dimensional mixer for 15 minutes. Then, 21 mg of magnesiumstearate was added and mixed for another 2 minutes in the threedimensional mixer. After mixing, the mixture was passed through a40-mesh sieve and tableted with a mechanical single-punch tabletingmachine at a pressure of 5 MPa, each tablet weighing 1050 mg. Thepressed large tablets were crushed and passed through a 10-mesh sieve,and dispensed into gelatin capsules at a loading of 350 mg per capsule.The dissolution rate was measured by a basket method at pH 6.0, at arotation speed of 100 rpm and at the selected time points of 5, 10, 15,20, 30, 45 and 60 minutes. The dissolution results of the formulationprepared by pulverizing palbociclib alone and of the formulationprepared by co-pulverizing palbociclib and tartaric acid were shown inFIG. 3.

Example 3 Preparation of a Solid Dispersion by Mixing Palbociclib withthe Acidic Material and Then with PVP-K30

100 mg of the API of palbociclib and 200 mg of tartaric acid wereweighed and placed into a 10 ml penicillin bottle, added with 2 ml ofpurified water, mixed and dissolved. 200 mg of PVP-K30 (manufactured byBASF, Germany, full name: povidone K30) was added to the solution anddissolved by ultrasound together with hand shaking. In a fume hood,water was volatilized by means of stirring under heating; and nitrogenwas introduced to facilitate water evaporation. Stop heating andstirring when the content of the penicillin bottle was gelatinous andthere was no more liquid reduction. It was placed into a vacuum dryer,overnight at 40° C., and removed the next day, and thereby, the soliddispersion was prepared.

Example 4 Preparation of a Solid Dispersion by Mixing Palbociclib withthe Acidic Material and Then with a Solid Carrier PVP-VA64

100 mg of the API of palbociclib and 200 mg of tartaric acid wereweighed and placed into a 10 ml penicillin bottle, added with 2 ml ofdouble distilled water, mixed and dissolved. 200 mg of PVP-VA64(manufactured by BASF, Germany, full name: Copovidone) was added to thesolution and dissolved by ultrasound together with hand shaking. In afume hood, water was volatilized by means of stirring under heating; andnitrogen was introduced to facilitate water evaporation. Stop heatingand stirring when the content of the penicillin bottle was gelatinousand there was no more liquid reduction. It was placed into a vacuumdryer, overnight for 18 hours at 40° C., and removed the next day, andthereby, the solid dispersion was prepared.

Example 5 Preparation of a Solid Dispersion by Mixing Palbociclib withthe Acidic Material and Then with a Solid Carrier Soluplus

100 mg of the API of palbociclib and 200 mg of tartaric acid wereweighed and placed into a 10 ml penicillin bottle, added with 2 ml ofdouble distilled water, mixed and dissolved. 200 mg of Soluplus(manufactured by BASF, Germany, full name: polyethylenecaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) wasadded to the solution and dissolved by ultrasound together with handshaking. In a fume hood, water was volatilized by means of stirringunder heating; and nitrogen was introduced to facilitate waterevaporation. Stop heating and stirring when the content of thepenicillin bottle was gelatinous and there was no more liquid reduction.It was placed into a vacuum dryer, overnight at 40° C., and removed thenext day, and thereby, the solid dispersion was prepared.

Example 6 Preparation of a Solid Dispersion by Mixing Palbociclib withthe Acidic Material and Then with a Solid Carrier HPMC-E5

100 mg of the API of palbociclib and 200 mg of tartaric acid wereweighed and placed into a 10 ml penicillin bottle, added with 2 ml ofdouble distilled water, mixed and dissolved. 200 mg of HPMC-E5(manufactured by BASF, Germany, full name: hydroxypropylmethylcelluloseE5) was added to the solution and dissolved by ultrasound together withhand shaking. In a fume hood, water was volatilized by means of stirringunder heating; and nitrogen was introduced to facilitate waterevaporation. Stop heating and stirring when the content of thepenicillin bottle was gelatinous and there was no more liquid reduction.It was placed into a vacuum dryer, overnight at 40° C., and removed thenext day, and thereby, the solid dispersion was prepared.

Example 7 Preparation of a Solid Dispersion by Mixing Palbociclib withthe Acidic Material and Then with a Solid Carrier HPMC-AS-HF

100 mg of the API of palbociclib and 200 mg of tartaric acid wereweighed and placed into a 10 ml penicillin bottle, added with 2 ml ofdouble distilled water, mixed and dissolved. 200 mg of HPMC-AS-HF(manufactured by BASF, Germany, full name: hydroxypropylmethylcelluloseAS-HF) was added to the solution and dissolved by ultrasound togetherwith hand shaking. In a fume hood, water was volatilized by means ofstirring under heating; and nitrogen was introduced to facilitate waterevaporation. Stop heating and stirring when the content of thepenicillin bottle was gelatinous and there was no more liquid reduction.It was placed into a vacuum dryer, overnight at 40° C., and removed thenext day, and thereby, the solid dispersion was prepared.

Example 8 Preparation of a Solid Dispersion by Mixing Palbociclib withthe Acidic Material and Hydrochloric Acid and Then with a Solid CarrierPVP VA64

125 mg of the API of palbociclib was weighed and placed into a 10 mlpenicillin bottle; 1.991 ml of double distilled water and 8.63 μl of 36%hydrochloric acid solution (having a density of 1.18 g/mL) were added,so that the molar ratio of hydrochloric acid to the API of palbociclibwas 1:1. Then 200 mg of tartaric acid was added and completely mixed anddissolved under the action of ultrasound. 100 mg of PVP VA64 was addedto the above solution and dissolved by ultrasound together with handshaking. In a fume hood, water was volatilized by means of stirringunder heating; and nitrogen was introduced to facilitate waterevaporation. Stop heating and stirring when the content of thepenicillin bottle was gelatinous and there was no more liquid reduction.It was placed into a vacuum dryer, overnight at 40 ° C., and removed thenext day, and thereby, the solid dispersion was prepared.

Example 9 Preparation of a Solid Dispersion by Mixing Palbociclib withthe Acidic Material and Phosphoric Acid and Then with a Solid CarrierPVP VA64

125 mg of the API of palbociclib was weighed and placed into a 10 mlpenicillin bottle; 2 ml of double distilled water and 27.3 mg ofphosphoric acid were added, so that the molar ratio of phosphoric acidto the API of palbociclib was 1:1. Then 200 mg of tartaric acid wasadded and completely mixed and dissolved under the action of ultrasound.100 mg of PVP VA64 was added to the above solution and dissolved byultrasound together with hand shaking. In a fume hood, water wasvolatilized by means of stirring under heating; and nitrogen wasintroduced to facilitate water evaporation. Stop heating and stirringwhen the content of the penicillin bottle was gelatinous and there wasno more liquid reduction. It was placed into a vacuum dryer, overnightat 40° C., and removed the next day, and thereby, the solid dispersionwas prepared.

Example 10

The palbociclib solid dispersion prepared with PVP-K30 in Example 3 andthe API of palbociclib both were sent for XRPD test. The XRPD test wasperformed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mgof sample was evenly tiled on a monocrystalline silicon sample tray andsubjected to the XRPD test with the following parameters: scanning range(2θ°): 3-40; scanning step (2θ°):0.0263; scanning time (seconds):46.665; K-Alpha wavelength (Å): 1.54060; K-Alpha2 wavelength (Å):1.54443; Power setting: 40 mA, 45 kV. The obtained XRPD pattern of theAPI of palbociclib was shown in FIG. 6; and the XRPD pattern of thesolid dispersion prepared with PVP-K30 was shown in FIG. 9.

Example 11

The palbociclib solid dispersion prepared with PVP-VA64 in Example 4 wassent for XRPD test. The XRPD test was performed with Panalytical'sXPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled ona monocrystalline silicon sample tray and subjected to the XRPD testwith the following parameters: scanning range (2θ°): 3-40; scanning step(2θ°):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength (Å):1.54060; K-Alpha2 wavelength (Å): 1.54443; Power setting: 40 mA, 45 kV.The obtained XRPD pattern was shown in FIG. 8.

Example 12

The palbociclib solid dispersion prepared with Soluplus in Example 5 wassent for XRPD test. The XRPD test was performed with Panalytical'sXPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled ona monocrystalline silicon sample tray and subjected to the XRPD testwith the following parameters: scanning range (2θ°): 3-40; scanning step(20θ°):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength (Å):1.54060; K-Alpha2 wavelength (Å): 1.54443; Power setting: 40 mA, 45 kV.The obtained XRPD pattern was shown in FIG. 10.

Example 13

The solid dispersion prepared with HPMC-E5 in Example 6 was sent forXRPD test. The XRPD test was performed with Panalytical's XPERT-3 X-raydiffractometer. About 10 mg of sample was evenly tiled on amonocrystalline silicon sample tray and subjected to the XRPD test withthe following parameters: scanning range (2θ°): 3-40; scanning step(2θ°):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength (Å):1.54060; K-Alpha2 wavelength (Å): 1.54443; Power setting: 40 mA, 45 kV.The obtained XRPD pattern was shown in FIG. 11.

Example 14

The solid dispersion prepared with HPMC-AS-HF in Example 7 was sent forXRPD test. The XRPD test was performed with Panalytical's XPERT-3 X-raydiffractometer. About 10 mg of sample was evenly tiled on amonocrystalline silicon sample tray and subjected to the XRPD test withthe following parameters: scanning range (2θ°): 3-40; scanning step(2θ°):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength (Å):1.54060; K-Alpha2 wavelength (Å): 1.54443; Power setting: 40 mA, 45 kV.The obtained XRPD pattern was shown in FIG. 7.

Example 15

62.5 mg of the solid dispersion prepared in Example 3 (containing 12.5mg of the API of palbociclib in proportion) and 12.5 mg of the API ofpalbociclib were weighed separately, placed into two 100 ml beakers,respectively, and marked with T1 and T2. 90 ml of phosphate buffer (pH6.0) was added to the two beakers respectively and a magnetic stir barwas placed therein. The two beakers were placed on a magnetic stirrerseparately. 1 ml of the solution was removed separately from each of thebeakers at the time points of 5, 10, 20, 40, and 60 minutes and filteredthrough a 0.45 μm micro PES polyethersulfone filter membrane. Thefiltrate was analyzed by high performance liquid chromatography, thecontent of the API of palbociclib was determined and the dissolutionpercentage was calculated. The results were shown in FIG. 4.

The description of the above examples is only intended to helpunderstanding the central concept of the present invention. It should benoted that those skilled in the art may make improvements andmodifications to the novel formulation and its preparation methodaccording to the present invention without departing from the principlesof the present invention, and such improvements and modifications alsofall within the scope of protection of the claims in the presentinvention.

The invention claimed is:
 1. A composition, wherein the compositioncomprises: an amorphous solid dispersion, wherein the amorphous soliddispersion comprises the following in an amorphous state: palbociclib ora pharmaceutically acceptable salt thereof; an acidic auxiliary materialcomprising at least two pharmaceutically acceptable acids, wherein thepharmaceutically acceptable salt of the palbociclib comprises one of theat least two pharmaceutically acceptable acids; and a hydrophilichigh-molecular weight material.
 2. The composition of claim 1, whereinthe composition is in the dosage form of a tablet or a capsule.
 3. Thecomposition of claim 1, wherein the palbociclib or the pharmaceuticallyacceptable salt thereof is present in an amount of 25 to 500 mg.
 4. Thecomposition of claim 1, wherein the palbociclib or the pharmaceuticallyacceptable salt thereof is present in an amount of 25, 50, 75, 100, 125,150, or 500 mg.
 5. The composition of claim 1, wherein at least one ofthe at least two pharmaceutically acceptable acids is selected from thegroup consisting of hydrochloric acid, sulfuric acid, phosphoric acid,and combinations thereof.
 6. The composition of claim 1, wherein the atleast two pharmaceutically acceptable acids comprise tartaric acid andan inorganic acid.
 7. The composition of claim 1, wherein thehydrophilic high-molecular weight material is one or more selected fromthe group consisting of povidone K30, copovidone VA64, polyethylenecaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer,hydroxypropylmethylcellulose E5, hydroxypropylmethylcellulose acetatesuccinate, hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin.
 8. The composition of claim 1, wherein thehydrophilic high-molecular weight material is copovidone VA64 orhydroxypropylmethylcellulose E5.
 9. A method for treating breast cancer,comprising: administering to a subject having breast cancer apharmaceutical composition, wherein the pharmaceutical compositioncomprises an amorphous solid dispersion, wherein the amorphous soliddispersion comprises the following in an amorphous state: palbociclib ora pharmaceutically acceptable salt thereof; an acidic auxiliary materialcomprising at least two pharmaceutically acceptable acids, wherein thepharmaceutically acceptable salt of the palbociclib comprises one of theat least two pharmaceutically acceptable acids; and a hydrophilichigh-molecular weight material.
 10. The method of claim 9, wherein thepharmaceutical composition is orally administered.
 11. The method ofclaim 9, wherein the palbociclib or the pharmaceutically acceptable saltthereof is present in an amount of 25 to 500 mg.
 12. The method of claim9, wherein the palbociclib or the pharmaceutically acceptable saltthereof is present in an amount of 25, 50, 75, 100, 125, 150, or 500 mg.13. The method of claim 9, wherein at least one of the at least twopharmaceutically acceptable acids is selected from the group consistingof hydrochloric acid, sulfuric acid, phosphoric acid, and combinationsthereof.
 14. The method of claim 9, wherein the at least twopharmaceutically acceptable acids comprise tartaric acid and aninorganic acid.
 15. The method of claim 9, wherein the hydrophilichigh-molecular weight material is one or more selected from the groupconsisting of povidone K30, copovidone VA64, polyethylenecaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer,hydroxypropylmethylcellulose E5, hydroxypropylmethylcellulose acetatesuccinate, hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin.
 16. The method of claim 9, wherein the hydrophilichigh-molecular weight material is copovidone VA64 orhydroxypropylmethylcellulose E5.
 17. The composition of claim 5, whereinat least one of the at least two pharmaceutically acceptable acids ishydrochloric acid or phosphoric acid.
 18. The composition of claim 17,wherein a molar ratio of the hydrochloric acid or phosphoric acid to thepalbociclib or a pharmaceutically acceptable salt thereof is 1:1. 19.The method of claim 13, wherein at least one of the at least twopharmaceutically acceptable acids is hydrochloric acid or phosphoricacid.
 20. The method of claim 19, wherein a molar ratio of thehydrochloric acid or phosphoric acid to the palbociclib or apharmaceutically acceptable salt thereof is 1:1.